Methods of protection against emesis in mammals by administration of a 3-alkoxy-thianaphthene-2-carboxamide

ABSTRACT

Emesis in mammals is prevented by administration of 3-alkoxy-thianaphthene-2-carboxamides in a daily dosage ranging from 50 to 500 μg/kg as determined by a physician or veterinarian. When administered to dogs in a daily dosage of 250 μg/kg, 100% protection is obtained against vomiting normally induced by subcutaneous administration of apomorphine.

This is a division of application Ser. No. 348,189, filed Apr. 5, 1973,now U.S. Pat. No. 3,862,320, which is a continuation-in-part of U.S.patent application Ser. No. 140,605, filed May 5, 1971, now U.S. Pat.No. 3,745,175, which in turn is a continuation-in-part of theapplication Ser. No. 845,509, filed July 28, 1969, now abandoned.

This invention relates to 3-alkoxy-thianaphthene-2-carboxamides and moreparticularly to such carboxamides, the dioxides thereof and thepharmaceutically acceptable acid addition salts and quaternary ammoniumsalts of such carboxamides.

The inventions also includes methods of treatment of emesis of mammalswith such compounds.

The 3-alkoxy-thianaphthene-2-carboxamides of this invention have theformula: ##SPC1##

In which R₁ and R₂ are the same or different and are hydrogen, loweralkoxy, preferably having less than 5 carbon atoms, halogen (such asfluorine, chlorine, bromine or iodine), nitro or amino. Examples oflower alkoxy are methoxy, ethoxy and isopropoxy. B is allyl or loweralkyl, preferably having less than 5 carbon atoms, such as methyl, ethyland n-propyl; and n is 1, 2 or 3. A is mono lower alkylamino, di loweralkylamino, a 5 or 6 membered heterocyclic nitrogenous monovalentradical with or without oxygen, nitrogen-lower alkyl, nitrogen-allyl oran additional nitrogen atom connected through a nitrogen atom of thehetercyclic radical to the terminal methylene group of formula (1) or amonovalent radical having the formula: ##SPC2##

In which m is 1 or 2 and R₃ is allyl or lower alkyl, preferably havingless than 5 carbon atoms. Preferably, all of the lower alkylaminoradicals and the lower alkyl groups of the 5 or 6 membered heterocyclicnitrogenous monovalent radical have less than 7 carbon atoms, such asmethyl, ethyl, propyl, isobutyl and amyl. Examples when A is aheterocyclic nitrogenous monovalent radical are piperidinyl,pyrrolidinyl, imidazolidinyl, piperazino and morpholino.

This invention also includes the 1,1-dioxides, and the pharmaceuticallyacceptable acid addition salts and the quaternary ammonium salts of the3-alkoxy-thianaphthene-2-carboxamides of formula (1). The acid additionsalts may be of organic acids, such as acetic acid, succinic acid orcitric acid or inorganic acids, such as hydrochloric acid, sulfuric acidor phosphoric acid. If the 3-alkoxy-thianaphthene-2-carboxamides ortheir derivatives of this invention have one or more asymmetric carbonatoms, they may exist as the dextro or levo forms or racemic mixtures.

The compositions of this invention are useful as antiemetics and asagents in alleviating behavior disturbances in mammals.

The preparation of the compositions of this invention comprises cyclinga substituted or unsubstituted alkyl 2-carbomethyoxymethylthio benzoatewith the aid of an alkali metal alcoholate, as sodium methylate, toobtain a substituted or unsubstituted alkyl3-hydroxythianaphthene-2-carboxylate which is alkylized by means of analkylizing agent such as dimethyl sulfate or ethyl p-toluene sulfonate.The substituted or unsubstituted 3-methoxythianaphthene-2-carboxylicacid obtained by saponification of the ester is then converted to anamide by the desired amine.

A more comprehensive understanding of this invention is obtained byreference to the following examples.

EXAMPLE I N-(DIETHYLAMINOETHYL)-3-METHOXY-THIANAPHTHENE-2-CARBOXAMIDE

Stage A. 2-carboxy-methylthio-benzoic acid

Into a 1 liter flask equipped with an agitator, a thermometer and adropping funnel, there is introduced 137 g (1 mole) of anthranilic acid,200 ml of water and 105 ml of concentrated hydrochloric acid. Themixture is heated to complete dissolution, and then 105 ml ofconcentrated hydrochloric acid is added. The hydrochloride of theanthranilic acid precipitates in the form of a very thick mass. It iscooled to about 0°C and into the pasty mixture there is poured drop bydrop a solution of 69 g (1 mole) of sodium nitrite in 140 ml of water.The temperature is maintained between 0° and 5°C.

A brown solution is obtained which is agitated for one hour between 0and 5°C. The excess hydrochloric acid is neutralized by the addition of150 g of potassium acetate, to obtain a pH of about 4.

The diazoic solution thus obtained is poured dropwise into a solutioncontaining 320 g of potassium xanthate (2 mole) in 440 ml of water. Theoperation is done at between 75° and 80°C. The nitrogen separatesrapidly and the solution becomes cloudy. After cooling, the product isprecipitated by the addition of 160 ml of hydrochloric acid. Theprecipitated product is drained and washed on a filter with water. Theproduct is then put in suspension in 400 ml of water, and 200 ml ofsodium hydroxide and the mixture is heated for 2 hours in a bain-marie.The solid dissolves, giving a brown-red solution. To this solution thereis added dropwise a solution of 132 g (0.9 mole + excess of 50%) ofchloracetic acid dissolved in 100 ml of water to which is added 140 mlof 30% sodium hydroxide.

The solution thus obtained is heated for 2 hours at reflux, the pH beingmaintained at about 3. It is then cooled and 16 ml of sodium hydroxideis added to take the pH to 7.8.

The solution is filtered, passed through charcoal and the acid isprecipitated with 150 ml of hydrochloric acid. There are obtained 153 g(yield: 72%) of 2-carboxy-methylthiobenzoic acid (m.p.: 214-215°C).

Stage B. Methyl-2-carbomethoxymethyl-thio-benzoate

Into a 2 liter flask equipped with a reflux refrigerant, there areintroduced 450 g of methyl alcohol, then in small portions, whilecooling, 232 g of 100% sulfuric acid and then 128 g of2-carbomethylthio-benzoic acid (0.6 mole). There is obtained a redsuspension which dissolves under heat. The mixture is refluxed for 9hours. There is then distilled one part of alcohol and the remainingsolution is poured into 4 liters of water containing 254 g of sodiumcarbonate. The methyl 2-carbomethoxy-methyl-thio-benzoate precipitates.It is drained, washed with water until the sulfate ions are eliminated,and air-dried. There are obtained 113 g of product, (m.p.: 49°-50°C)(yield: 65%).

Stage C. Methyl 3-hydroxy-thianaphthene-2-carboxylate

In a 500 ml flask equipped with a reflux refrigerant there is dissolved9 g of sodium in 180 ml of methyl alcohol. The mixture is cooled andthere is added in small portions 95 g (0.40 mole) of methyl2-carbomethoxy-methyl-thio-benzoate. There is observed no dissolution,but there is immediate transformation of the ester in sodium salt ofthianaphthene formed in the form of a thick yellow precipitate. When theintroduction is terminated, the mixture is allowed to react for 4 hoursat room temperature. The precipitate is redissolved by the addition of1.8 liter of water. The solution is filtered and passed throughcharcoal. The methyl 3-hydroxy-thianaphthene-2-carboxylate is thenprecipitated by the addition of 50 ml of acetic acid. It is drained,washed with water and dried. There are obtained 73 g of product. (yield:89%) (m.p.: 105°-106°C).

Stage D. Methyl-3-methoxy-thianaphthene-2-carboxylate

In a flask equipped with an impervious agitator, a reflux refrigerantand a thermometer, there is dissolved 50 g (0.24 mole) of methyl3-hydroxy-thianaphthene-2-carboxylate in 250 mml of acetone at about40°C. There is added 33 g of methyl sulfate, then 33 g of potassiumcarbonate. There is obtained a suspension which is refluxed for 3 hours.One part of the acetone is distilled and the residue reclaimed by theaddition of 500 ml of water. The methyl3-methoxy-thianaphtene-2-carboxylate precipitates. It is drained, washedwith water and dried. 52 G of product is obtained. (yield: 99%) (m.p.:66°-67°C).

Stage E. 3-methoxy-thianaphthene-2-carboxylic acid

In a 250 ml flask equipped with a reflux refrigerant, there is dissolved52 g (0.23 mole) of methyl 3-methoxy-thianaphthene-2-carboxylate in 75ml of 95% alcohol. There is added 24 ml of sodium hydroxide and themixture is brought to reflux in a water bath. The sodium salt ofthianaphthene-carboxylic acid formed precipitates and forms a mass atthe start of heating. The reflux is maintained for two hours and theprecipitate recovered in 750 ml of water. The solution obtained isfiltered and passed through charcoal, and then the3-methoxy-thianaphthene-2carboxylic acid is precipitated by 25 ml ofhydrochloric acid. The product is drained, washed in water until thechlorine ions are eliminated and dried at about 50°C. There are obtained46 g of product. (yield: 96%) (m.p.: 182°-183°C).

Stage F. 3-Methoxy-thianaphthene-2-carbonyl chloride

Into a 250 ml flask equipped with a reflux refrigerant, there areintroduced 50 g of thionyl chloride and 44 g (0.21 mole) of3-methoxy-thianaphthene-2-carboxylic acid. The mixture is heated in awater-bath at 50°C. until it is completely dissolved. The excess thionylchloride is then distilled under vacuum. The solid residue is reclaimedwith 50 ml of petroleum ether. The 3-methoxy-thianaphthene-2-carbonylchloride is drained, washed with petroleum ether and dried under vacuum.There are obtained 47 g of product. (yield: 99%) (m.p.: 93°-94°C).

Stage G. N-(diethylaminoethyl)-3-methoxy-thianaphthene-2-carboxamide

In a 500 ml flask with thermometer, agitator and dropping funnel, thereare introduced 24 g (0.205 mole) of diethylaminoethylamine and 150 ml ofmethylethylketone. It is cooled at 5° C and there is then added in smallportions 3-methoxy-thianaphthene-2-carbonyl chloride. At the end of 2hours the thianaphthene-carboxamide hydrochloride formed partiallycrystallizes. It is recovered in 500 ml of water.

The solution obtained is filtered and the base is precipitated by theaddition of 30 ml of ammonia. It is decanted, and the aqueous solutionis extracted with ether. The organic solution obtained is washed inwater and dried on potassium carbonate. The ether is then completelydistilled under vacuum. There are obtained 46 g ofN-(diethylaminoethyl)-3-methoxy-thianaphthene-2-carboxamide (yield: 84%)in the form of an orange-red liquid.

Stage H.

The base obtained in the preceding stage is dissolved in 40 ml ofabsolute alcohol, and 16 g of 85% of phosphoric acid dissolved in 40 mlof absolute alcohol is added. The phosphate ofN-(diethylaminoethyl)-3-methoxy-thianaphthene-2-carboxamideprecipitates. It is drained, washed with 50 ml of absolute alcohol anddried at 60°C. It is a white solid. (m.p.: 173°-174°C).

EXAMPLE IIN-(1-ETHYL-2-PYRROLIDYLMETHYL)-3-METHOXY-THIANAPHTHENE-2-CARBOXAMIDE

Stages A through F are the same as those described in Example I.

Stage G.

Into a 500 ml flask equipped with an agitator and a thermometer, thereare introduced 26 g (0.205 mole) of 1-ethyl-2-aminomethylpyrrolidine and150 ml of methylethylketone, and while maintaining the temperaturebetween 5° and 10° C there are added in small portions, 47 g (0.207mole) of 3-methoxy-thianaphthene-2-carbonyl chloride.

After the introduction is terminated, agitation is continued whileallowing the temperature to mount. The solution obtained is thenrecovered with 500 ml of water. All the solvent is removed and the baseis precipitated by the addition of 30 ml of ammonia. This base isextracted with ether and the ether dried after washing in water onpotassium carbonate.

The solvent is then completely distilled under vacuum. There areobtained 58 g ofN-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-thianaphthene-2-carboxamide inthe form of a violet liquid. (yield: 89%)

Stage H. Phosphate ofN-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-thianaphthene-2-carboxamide

There are dissolved 55 g (0.17 mole) of1-ethyl-2-pyrrolidylmethyl-3-methoxy-thianaphthene-2-carboxamide in 100ml of 95% alcohol and to that solution is added 20 g of 85% phosphoricacid dissolved in 100 ml of alcohol at 95°C. The phosphate ofN-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-thianaphthene-2-carboxamideformed crystallizes. It is drained and washed with 50 ml of 95% alcoholand dried at room temperature. It is a white solid. (m.p.: 177°-178°C).

EXAMPLE IIIN-(DIETHYLAMINOETHYL)-1,1-DIOXY-3METHOXY-THIANAPHTHENE-2-CARBOXAMIDE

Stage A. 2-(carboxymethyl-sulfonyl)-benzoic acid

Into a 3 liter flask equipped with a reflux and agitator, there areintroduced 178 g (0.84 mole) of 2-carboxymethylthiobenzoic acid and 50ml of acetic acid. There is obtained a suspension to which 550 ml ofhydrogen peroxide solution to 102 volumes is added in small portions.The mixture is heated at 70° for 6 hours. The solution obtained becomesyellow, then greenish. It is heated for 4 hours at reflux until theoxygen is completely released. After the acetic acid and the water havebeen removed under vacuum, the 2-(carboxy-methyl-sulfonyl)-benzoic acidformed crystallizes. It is drained, placed in suspension in 150 ml ofbenzene, again refiltered and washed on the filter with benzene. Thereare obtained 191 g of product. (yield: 93%) (m.p.: 161°-162°C).

Stage B. Methyl 2-(carbomethoxymethylsulfonyl)-benzoate

Into a 2 liter flask equipped with a reflux and agitator, there areintroduced 585 g of methyl alcohol, then there is poured in smallportions 310 g of 100% sulfuric acid and 191 g (0.78 mole) of2-carboxymethylsulfonyl-benzoic acid are added. The mixture is refluxedfor 9 hours. After one part of the alcohol has been removed undervacuum, the residue is poured into 5 liters of water containing 335 g ofsodium carbonate. The ester formed precipitates. It is desired, washedin water until the sulphate ions are eliminated and dried at 40°C. Thereare obtained 169 g of methyl 2-(carbomethoxymethylsulfonyl)-benzoate.(yield: 80%) (m.p.: 102°-103°C).

Stage C. Methyl 1,1-dioxy-3-hydroxythianaphthene-2-carboxylate

In a 1 liter flask equipped with an agitator and a reflux andrefrigerant there are dissolved 14 g of sodium (0.62 mole) in 500 ml ofmethyl alcohol. To the solution of sodium methylate obtained, there areadded 169 g (0.62 mole) of methyl 2-carbomethoxymethylsulfonyl benzoate.The product dissolves progressively. Agitation is continued constantlyfor 41/2 hours at room temperature. Then 5 liters of water are added.The methyl 1,1-dioxy-3-hydroxy-thianaphthene-2-carboxylate is thenprecipitated by the addition of hydrochloric acid. It is drained, washedwith water until the chloride ions are eliminated and dried at ordinarytemperature. There are obtained 126 g (yield: 84.5%) of product meltingat 189_("-190)°C.

Stage D. Methyl 1,1-dioxy-3-chloro-thianaphthene-2-carboxylate

Into a 500 ml flask equipped with a reflux refrigerant, there areintroduced 132 g (0.55 mole) of1,1-dioxy-3-hydroxy-thianaphthene-2-methyl carboxylate, then 264 g ofthionyl chloride and 5.5 ml of pyridine. A slurry is obtained whenheated at reflux on a bain-marie. Heating is continued for 4 hours. Thenthe excess of thionyl chloride is removed. There remains 216 g of acrystallized, yellow product which is recovered with 400 ml of petroleumether, drained and washed with 350 ml of petroleum ether and driedquickly. This product formed of methyl1,1-dioxy-3-chloro-thianaphthene-2-carboxylate is put immediately intoreaction by the following step.

Stage E. Methyl 1,1-dioxy-3-methoxy-thianaphthene-2-carboxylate

In a 1 liter flask equipped with an impervious agitator, a refluxrefrigerant and a thermometer, there are dissolved 32 g (2.5 × 0.35mole) of sodium in 400 ml of methyl alcohol. The product of Stage D isthen added, avoiding a temperature rising up to 20°C. There is obtainedan orange solid. After 4 hours, 4 liters of water are added. Theprecipitated product is drained, washed with water and dried. There areobtained 30 g (yield: 21%) of methyl1,1-dioxy-3-methoxy-thianaphthene-2-carboxylatethianaphthene-2-carboxylate (m.p.: 162°-163°C).

Stage F.N-(diethylaminoethyl)-1,1-dioxy-3-methoxy-thianaphthene-2-carboxamide

Into a 500 ml flask equipped with an agitator, a thermometer and adropping funnel there are introduced 33 g (0.13 mole) of methyl1,1-dioxy-3-methoxy-thianaphthene-2-carboxylate and 165 ml of ethyleneglycol.

This is heated at 110°C to obtain a dissolution of the product and thetemperature is allowed to return to 30°C. At that time there are addeddropwise through the dropping funnel 18 g (0.15 mole) ofdiethylaminoethyl-amine. The reaction is violent. The temperature risesrapidly to 45°-50°C. When the introduction is finished, agitation iscontinued for an hour at about 25°C. Then 600 ml of water are added andthe product obtained is drained. This product is recrystallized in 100ml of absolute alcohol. There are obtained 39 g (yield: 81%) ofN-(diethylaminoethyl)-1,1-dioxy-3-methoxy-thianaphthene-2-carboxamide(m.p.: 135°-136°C).

Stage G. Hydrochloride ofN-(diethylaminoethyl)-1,1-dioxy-3-methoxy-thianaphthene-2-carboxamide

The product obtained in the preceeding Stage F is dissolved in 150 ml ofabsolute alcohol and there is added an alcoholic solution of 3.4 g ofgaseous hydrochloric acid in 1 liter of alcohol. The hydrochloride ofN-(diethylaminoethyl)-1,1-dioxy-3-methoxy-thianaphthene-2-carboxamideformed precipitates. It is drained, washed in alcohol and air-dried. Itis a white solid. (m.p.: 203°C) (yield: 94%).

EXAMPLE IVN-(1-ETHYL-2-PYRROLIDYLMETHYL)-3-METHOXY-THIANAPHTHENE-1,1-DIOXY-2-CARBOXAMIDE

Stages A through E are the same as those described in Example III.

Stage F.

Into a 1 liter flask equipped with an agitator, a thermometer and adropping funnel, there are introduced 57 g (0.224 mole) of methyl3-methoxy-thianaphthene-1,1-dioxy-2-carboxylate and 285 ml of ethyleneglycol. The mixture is heated to 40°C and at that temperature there areadded dropwise 29 g (0.225 mole) of 1-ethyl-2-aminomethylpyrrolidine.After the introduction is terminated, agitation is continued for 3hours. The mixture is cooled and 1 liter of water is added. The solidproduct obtained is drained, washed with water and dried. Afterrecrystallization of this product in alcohol, there are obtained 61 g(yield: 78%) ofN-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-thianaphthene-1,1-dioxy-2-carboxamide.(m.p.: 112°-113°C).

Stage G. Hydrochloride ofN-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-thianaphthene-1,1-dioxy-2-carboxamide

44 G ofN-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-thianaphthene-1,1-dioxy-2-carboxamideare dissolved in 100 ml of absolute alcohol. To this solution are added4.6 g of gaseous hydrochloric acid dissolved in 30 ml of alcohol. THehydrochloride ofN-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-thianaphthene-1,1-dioxy-2-carboxamideformed is drained, washed on a filter with absolute alcohol and dried.There are obtained 47 g of a white solid. (yield: 96.5%) (m.p.:212°-213°C).

EXAMPLE vN-(DIETHYLAMINOETHYL)-3,5,6-TRIMETHOXY-THIANAPHTHENE-2-CARBOXAMIDE

Stage A. Methyl 3,4-dimethoxy-6-nitro-benzoate

In a 2 liter flask equipped with an agitator, there are introduced 560ml of 40% nitric acid, then 144 g (0.74 mole) of methyl 3,4dimethoxybenzoate. Agitation is maintained at room temperature. Little by little,the liquid becomes thicker and at the end of four hours there isobtained a thick paste. It is allowed to stand overnight. The nitricderivative is diluted with a little water, drained and washed with wateruntil neutralized. There are obtained 144 g (yield: 81%) of methyl3,4-dimethoxy-6-nitro-benzoate. (m.p.: 143°-144°C).

Stage B. Methyl 3,4-dimethoxy-6-aminobenzoate

In an hydrogenating autoclave, there are placed 144 g of methyl3,4-dimethoxy-6-nitro-benzoate, 300 ml of tetrahydrofuran and 3 coffeespoonfuls of Raney nickel. Hydrogenation occurs at about 35°C. In 20minutes, the pressure drop is 80 kg. It is cooled, the nickel filtered,and the tetrahydrofuran removed under vacuum. There are obtained 123 g(97%) of methyl 3,4-dimethoxy-6-aminobenzoate. (m.p.: 130°C).

Stage C. 2-Carboxymethyl-thio-4,5-dimethoxy benzoic acid 3,4crystallizes.

Into a 2 liter flask equipped with an agitator, a thermometer and adropping funnel, there are introduced 113 g (0.54 mole of methyl 3,4-dimethoxy-6-amino-benzoate, 215 ml of water and 107 ml of concentratedhydrochloric acid. A thick suspension is obtained which is heated tocomplete dissolution, then cooled to 0° C so that the hydrochlorideformed crystalizes. Then there is introduced dropwise a solution of 37 gof sodium nitrite in 275 ml of water, the temperature being maintainedbetween 0° and 5° C. The precipitate dissolves progressively. There isobtained a clear solution which is neutralized by the addition of 18 gof potassium carbonate, so as to raise the pH to 4.

In a a 2 liter flask equipped with an agitator, a thermometer and adropping funnel, there are dissolved 128 g of potassium xanthate in 220ml of water. The solution is heated at 75° C and then pours slowly,dropwise, the diazoic solution obtained previously. The xanthogenicester formed separates in the form of an oily bed. It is allowed tocool. The organic product is extracted in ether. The etherized solutionis washed in soda, then in water and dried on sodium sulfate. 160 g ofthe xanthogenic derivative is obtained (yield: 94%).

To the xanthogenic derivative is added a hydroalcoholic solution ofpotash obtained by dissolving 130 g of potassium hydroxide in a mixtureof 415 ml of alcohol and 70 ml of water. It is heated at reflux andcooled. The solution is diluted with 3 liters of water and the acidprecipitated with 180 ml of concentrated hydrochloric acid.

After cooling, it is drained and washed with water until the chlorineions disappear. The raw and moist product thus obtained is immediatelyput in reaction with the sodium chloroacetate. By adding to this product48g of chloracetic acid dissolved in 36 ml of water and 50 ml of sodaand heating the mixture obtained at reflux for 3 hours, there isobtained a cloudy solution which is diluted with 2 liters of water andfiltered after passage through charcoal. The2-carboxy--methylthio-4,5--dimethoxy benzoic acid formed is thenprecipated by the addition of 70 ml of concentrated hydrochloric acid.It is drained, washed in water until the chlorine ions are eliminatedand dried at ordinary temperature. There are obtained 111g of product(yield: 77%) (m.p.: 227°-228° C).

Stage D. Methyl 2-(carbomethoxymethylthio)-4,5-dimethoxy-benzoate

Into a 1 liter flask equipped with a reflux refrigerant, are put 300 gof methyl alcohol and 164 g of 100% sulfuric acid are poured in, insmall portions. Then 110 g of 2-carboxymethylthio-4,5-dimethoxy-benzoicacid are added. The organic acid dissolves little by little and afterheating for 3 hours, the ester begins to crystalize. The reflux iscontinued for 9 hours. The reaction mixture is then poured into 3 litersof water containing 195 g of sodium carbonate. The methyl2-carbomethoxymethylthio-4,5-dimethoxy-benzoate formed is drained,washed in water until the sulfate ions are eliminated, and air-dried.There are obtained 105 g of product (yield: 86%) (m.p.: 120°-121° C).

Stage E. Methyl-3-hydroxy-5,6-dimethoxy-thianaphthene-2-carboxylate

In a 1 liter flask equipped with an impervious agitator, a refluxrefrigerant and a thermometer, there are dissolved 8 g of sodium of 315ml of alcohol. Then 105 g (0.35 mole) of methyl 2-carbomethoxymethylthio-4,5-dimethoxy-benzoate are introduced in smallportions. The ester begins to dissolve and then the sodium saltprecipitates rapidly.

When the introduction is ended, the mixture is heated at reflux for 3hours. The precipitate is then redissolved in 3 liters of water. Thereremains a insoluble gelatinous substance which is filtered. The methyl3-hydroxy-5,6-dimethoxy thianaphthene-2-carboxylate formed isprecipitated by the addition of 70 ml of acetic acid. The precipitate isdrained, washed in water and dried at 60° C. There are obtained 82 g ofproduct (yield: 85%) (m.p.: 184°-185° C).

Stage F. Methyl 3,5,6-trimethoxy-thianaphthlene-2-carboxylate

In a 2 liter flask equipped with an impervious agitator, a refluxrefrigerant and a thermometer, there are introduced 82 g (0.305 mole) ofmethyl 3-hydroxy-5,6-dimethoxy--thianaphthene-2-carboxylate, 575 ml ofacetone and 42 g of potassium carbonate. There are added 42 g of methylsulfate in small portions. The mixture is heated at reflux for 5 hours.Then the acetone is distilled and the residue recovered with 2 liters ofwater. The methyl 3,5,6-trimethoxy-thianaphthene-2-carboxylate formedprecipates. It is drained, washed with water and air-dried. There areobtained 83 g of product melting at 132°-133° C (yield: 95%).

Stage G.N-(diethylaminoethyl)-3,5,6-trimethoxy-thianaphthene-2-carboxamide

In a 250 ml flask with a Vigreux column of 40 cm, there are introduced32 g (0.113 mol) of methyl 3,5,6-trimethoxy-thianaphthene-2-carboxylate,90 ml of xylene, 20 g of diethylaminoethylamine and 5.7 g of aluminumisopropylate. There is obtained a suspension which is heated gently soas to distill the alcohol formed in the form of its azeotrope with thexylene. The duration of the reaction is 1 1/2 hours in total. Aftercooling, the solution is recovered with 400 ml of water and 30 ml ofconcentrated hydrochloric acid.

The N-(diethylaminoethyl)-3,5,6-trimethoxy-thianaphthene-2-carboxamideformed passes in the aqueous solution in the form of hydrochloride. Theaqueous solution is filtered and the amine is precipated with 35 ml ofsoda until turning red to phenolphthalein.

After cooling, it is drained, washed with water until the chlorine ionsare eliminated and dried at 40° C. There are obtained 23 g (yield: 56%)of N-(diethylaminoethyl)-3,5,6-trimethoxy-thianaphthene-2-carboxamide(m.p.: 128°-129°C).

EXAMPLE VIN-(1-ETHYL-2-PYRROLIDYLMETHYL)-3,5,6-TRIMETHOXY-THIANAPHTHENE-2-CARBOXAMIDE

stages A through F are the same as those described in Example V.

Stage G.N-(1-ethyl-2-pyrrolidylmethyl)-3,5,6-trimethoxy-thianaphthene-2-carboxamide

In a 1 liter flask with a 40 cm Vigreux column, there are introduced 85g (0.3 mole) of methyl 3,5,6-trimethoxy-thianaphthene-2-carboxylate, 250ml of xylene, 46 g of 1-ethyl-2-aminomethyl-pyrrolidine and 15.5 g ofaluminum isopropylate and the flask is gently heated so as to distillthe alcohol in the form of its azeotrope with xylene. The reaction lastsabout 1 hour. The solution obtained is recovered, after cooling, with600 ml of water and 85 ml of concentrated hydrochloric acid. The aqueoussolution is decanted and the xylene layer is washed twice withhydrochloric water.

The aqueous solutions are joined, filtered with charcoal and the base isprecipitated with 120 ml of sode lye. It is a liquid which is decanted.The aqueous solution is extracted in methylene chloride and the organicsolution dried on potassium carbonate.

The solvent is then distilled under vacuum to a constant weight. Theresidue is recrystalized in 60 ml of isopropyl alcohol. There areobtained 29 g (yield: 30%) ofN-(1-ethyl-2-pyrrolidylmethyl)-3,5,6-trimethoxy-thianaphthene-2-carboxamide(m.p.: 113°-114° C).

EXAMPLE VIIN-(DIETHYLAMINOETHYL)-3-METHOXY-5-AMINO-THIANAPHTHENE-2-CARBOXAMIDE

Stage A. 2-carboxymethylthio-5-nitrobenzoic acid

In a 5 liter flask equipped with an impervious agitator, a refluxrefrigerant and a thermometer, there are introduced 146 g (0.72 mole) of2-chloro-5-nitro-benzoic acid and 2200 ml of cellosolve. There isobtained a solution to which is added 181 g of sodium bicarbonate and 66g of thio-glycolic acid. The mixture is refluxed. There is very rapidprecipitation of the sodium salt of the carboxymethylthio acid formed.After 3 1/2 hours of reflux, the heating is stopped, and the sodium saltis cooled, drained and washed on a filter with 200 ml of cellosolve.This salt is then redissolved in water and the acid is precipitated with145 ml of concentrated hydrochloric acid. It is drained, washed withwater until the chloride ions are eliminated and dried at 50° C. Thereare obtained 159 g (yield: 86%) of 2-carboxymethylthio-5-nitro-benzoicacid (m.p.: 216°-217° C).

Stage B. Methyl 2 (carbomethoxymethylthio)-5-nitro-benzoate

In a 2 liter flask equipped with a reflux and refrigerant, there areintroduced 465 g of methyl alcohol and 250 g of sulfuric acid poured insmall portions. There are added 159 (0.62 mole) of2-carbomethoxymethylthio-5-nitro-benzoic acid. The mixture is refluxedfor 9 hours. It is cooled and the reaction mixture is poured into 6liters of water containing 270 g of sodium carbonate.

The methyl 2-(carbomethoxymethylthio)-5-nitro-benzoate formed isdrained, washed with water until the sulfate ions are eliminated anddried at 40° C. There are obtained 170 g of product (yield: 96%) (m.p.:116°-120° C)

Stage C. Methyl 3-hydroxy-5-nitro-thianaphthene-2-carboxylate

In a two-tube, 3 liter flask, there are dissolved 13.7 g of sodium in510 ml of methyl alcohol; then there are mounted on the flask animpervious agitator, a reflux, refrigerant and a thermometer. There areintroduced 170 g (0.6 mole) of methyl2-carbomethoxymethylthio-5-nitro-benzoate in small portions.

Agitation is continued for 5 hours. Then the thianaphthene formed isprecipitated by the addition of 5 liters of water and 300 ml of aceticacid. The product obtained is drained, washed in water until neutralizedand dried at 50° C. There are obtained 58 g (yield: 98%) of methyl3-hydroxy-5-nitro-thianaphthene-2-carboxylate (m.p.: 215° C).

Stage D. Methyl-3-methoxy-5-nitro-thianaphthene-2-carboxylate

In a 3 liter flask equipped with an impervious agitator, a refluxrefrigerant and a thermometer, there are introduced 128 g (0.50 mole) ofmethyl 3-hydroxy-5-nitro-thianaphthene-2-carboxylate, 900 ml of acetone,70 g of methyl sulfate and 70 g of potassium carbonate. A suspension isobtained which is heated at 40° C. It forms a yellow mass which becomesmore and more thick. After 12 hours of heating, 9 liters of water areadded which dissolve the mineral salts. The methyl3-methoxy-5-nitro-thianaphthene-2-carboxylate thus formed is drained,washed with water and dried at 40° C. There are obtained 130 g ofproduct (yield: 96%) melting at 163° C.

Stage E.

In a flask equipped with an agitator and a thermometer, there areintroduced 106 g (0.4 mole) of methyl3-methoxy-5-nitro-thianaphthene-2-carboxylate, 630 ml of ethylene glycoland 30 g of diethylaminoethylenediamine. There is obtained a thick massdifficult to agitate. The reaction mixture is maintained at 60° C for 24hours. The precipitate is then recovered with 3 liters of water andredissolved by the addition of acetic acid. There remains an unimportantinsoluble which is filtered. The solution is then treated with 200 ml of24% ammonia. TheN-(diethylaminoethyl)-3-methoxy-5-nitro-thianaphthene-2-carboxamide isfiltered, washed on a filter with water and dried. It is a white solid(m.p.: 175° C).

Stage F.N-(diethylaminoethyl)-5-amino-3-methoxy-thianaphthene-2-carboxamide

The nitrited derivative obtained in stage E is placed in an autoclaveunder pressure with 300 ml of tetrahydrofuran and two coffee spoons ofRaney nickel. Hydrogenation is carried out at a temperature of 40° C andis completed in about 1 hours.

After cooling, the solution of tetrahydrofuran is filtered to separatethe Raney nickel, is concentrated on a water-bath and the productobtained is precipitated by the addition of 350 ml of water. It is inthe form of pale yellow crystals (m.p.: 104° C). The hydrochloride ofthis corresponding base is a white solid melting at 185° C.

EXAMPLE VIIIN-(DIMETHYLAMINOETHYL)-3-METHOXY-5-AMINO-THIANAPHTHENE-2-CARBOXAMIDE

Stages A through D are the same as described in Example VII.

Stage E. 3-Methoxy-5-nitro-thianaphthene-2-carboxylic acid

In a 2 liter flask equipped with a reflux refrigerant, there areintroduced 140 g (0.545 mole) of methyl3-methoxy-5-nitro-thianaphthene-2-carboxylate, 425 ml of alcohol, 425 mlof water and 60 ml of soda lye (0.545 mole + 10% excess). The mixture isheated for 4 hours in a bain-marie. The sodium salt precipitates. Theacid is precipitated by adding gently 60 ml of concentrated hydrochloricacid. The gelatinous mass obtained is agitated for several hours until acrystalized product is obtained. The3-methoxy-5-nitro-thianaphthene-2-carboxylic acid is drained, washedwith water and dried at 60° C. (yield: 98%) (m.p.: 262°-265° C).

Stage F. 3-Methoxy-5-nitro-thianaphthene-2-carbonyl chloride

In a 500 ml flask equipped with a reflux refrigerant, 174 g of thionylchloride (4 × 0.366 mole) are introduced and then a half portion of 93g(0.366 mole) of the organic acid is added before reacting. Partialdissolution of the acid is observed at the end of one hour. Aftercooling, the remaining portion of acid is added. It is heated to 80° C.When the reaction is completed, the excess thionyl chloride is distilledunder vacuum. There are obtained 98 g (99%) of3-methoxy-5-nitro-thianaphthene-2-carbonyl chloride. (m.p.: 167°-170°C).

Stage G.N-(dimethylaminoethyl)-3-methoxy-5-nitro-thianaphthene-2-carboxamidehydrochloride

In a 1 liter flask equipped with an agitator and a thermometer, thereare introduced 470 ml of chloroform and 50 g of dimethylformamide. It iscooled to between +5 and +10° C and 110 g of3-methoxy-5-nitro-thianaphthene-2-carbonyl chloride are addedfractionally so as to maintain the temperature. The introduction takesabout 2 hours. Agitation is continued overnight at room temperature. Thefollowing day a light insoluble is filtered and 30 ml of concentratedhydrochloric acid are added to the chloroform solution. TheN-(dimethylaminoethyl)-3-methoxy-5-nitro-thianaphthene-2-carboxamidehydrochloride precipitates in the form of a yellow product which isdrained and dried at 50°C (yield: 66%) (m.p.: 186°C).

Stage H.N-(dimethylaminoethyl)-3-methoxy-5amino-thianaphthene-2-carboxamidedihydrochloride

96 G ofN-(dimethylaminoethyl)-3-methoxy-5-nitro-thianaphthene-2-carboxamidehydrochloride in 410 ml of water in the presence of 2 coffee spoons ofRaney nickel are hydrogenated under pressure at a temperature of 60°C.After filtration of the nickel, the solution is made alkaline with 50 mlof 30% ammonia. The base precipitates. It is drained, washed with waterand dried. There are obtained 70 g of product.

The product is redissolved in 375 ml of absolute alcohol, filtered onplant charcoal, and the solution is acidified by an alcohol solution ofhydrochloric acid. TheN-(dimethylaminoethy)-3-methoxy-5-amino-thianaphthene-2-carboxamidedihydrochloride thus formed is drained, washed with alcohol and dried.There are obtained 60 g (yield: 61%) of white crystals (m.p.: 210°C).

EXAMPLE IX RACEMICN-(1-ETHYL-2-PYRROLIDYLMETHYL)-3-METHOXY-5-AMINO-THIANAPHTHENE-2-CARBOXAMIDE

Stages A through D are the same as described in Example VII.

Stage E.N-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-5-nitro-thianaphthene-2-carboxamide

In a 2 liter flask equipped with an agitator and a thermometer, thereare introduced 100 g (0.4 mole) of methyl3-methoxy-5-nitro-thianaphthene-2-carboxylate, 640 ml of ethylene glycoland 64 g of 1-ethyl-2-aminomethyl-pyrolidine. The mixture is allowed tostand 10 days at 60°C and then the precipitate is recovered with from2.5 to 3 liters of water and redissolved by the addition of acetic acid.The base is then precipitated by the addition of 200 ml of ammonia.There are obtained 47 g ofN-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-5-nitro-thianaphthene-2-carboxamide(yield: 45.5%) (m.p.: 96°C).

Stage F.N-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-5-amino-thianaphthene-2-carboxamide

47 G of1-ethyl-2-pyrrolidylmethyl-3-methoxy-5-nitro-thianaphthene-2-carboxamidedissolved in 140 ml of tetrahydrofuran in the presence of 2 coffeespoons of Raney nickel are hydrogenated under pressure at a temperatureof 60°C. After filtration of the nickel, the tetrahydrofuran isdistilled and there remain 68 g ofN-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-5-amino-thianaphthene-2-carboxamidewhich are recovered with 100 ml of methylene chloride.

The methylene chloride is dried with sodium sulfate, then distilledunder vacuum to a constant weight. The base obtained is then dissolvedin warm alcohol and a solution of 14 ml of dry hydrochloric acid in 100ml of absolute alcohol is added. The dihydrochloride ofN-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-5-amino-thianaphthene-2-carboxamideformed precipitates. It is dried at low temperature, washed and dried atroom temperature. White crystals are obtained (m.p.: 195°C).

EXAMPLE X LEVON-(1-ETHYL-2-PYRROLIDYLMETHYL)-3-METHOXY-5-AMINO-THIANAPHTHENE-2-CARBOXAMIDE

Stages A through F are the same as those described in Example VIII.

Stage G. LevoN-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-5-nitro-thianaphthene-2-carboxamide

In a flask equipped with an agitator and a thermometer, there areintroduced 55 g (0.427 mole) of levo 1-ethyl-2-amino-methyl-pyrrolidineand 470 ml of chloroform. A solution is obtained to which is addedfractionally, 116 g (0.427 mole) of3-methoxy-5-nitro-thianaphthene-2-carbonyl chloride in powdered form at10°-12°C. When the introduction is completed, the temperature is allowedto rise and agitation is continued for several hours. After the additionof 200 ml of water, all of the chloroform is distilled. Thehydrochloride crystalizes. There are added 250 ml of water and heatingis continued to total dissolution. There remains an insoluble which isfiltered with heat (9 g). The hydrochloride crystalizes on cooling. Itis redissolved by heat and 43 ml of soda lye are added. The baseprecipitates. After cooling, it is drained, washed with water and driedat 50°C. There are obtained 143 g (yield: 92%) of levoN-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-5-nitro-thianaphthene-2-carboxamide(m.p.: 105°-106°C).

Stage H. LevoN-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-5-amino-thianaphthene-2-carboxamide

127 G (0.349 mole) of levoN-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-5-nitro-thianaphthene-2-carboxamidedissolved in 350 ml of water and 29.5 ml of concentrated hydrochloricacid in the presence of 2 coffee spoons of Raney nickel are hydrogenatedunder pressure at a temperature of 55°C. After filtration of the nickel,the amine base is precipitated with 60 ml of ammonia and recovered withmethylene chloride. The aqueous solution is extracted in methylenechloride and the organic solution is dried with potassium carbonate. Themethylene chloride is then distilled under vacuum. The base obtained isrecrystalized in acetonitrile and then in dioxan. The base obtained ispurified by passage through dihydrochloride and again through the freebase. There are obtained 47.5 g (yield: 40%) of levoN-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-5-amino-thianaphthene-2-carboxamide(m.p.: 101°-102°C); [α]_(D) = -45° (sol. 5% dimethylformamide).

EXAMPLE XI DEXTRON-(1-ETHYL-2-PYRROLIDYLMETHYL)-3-METHOXY-5-AMINO-THIANAPHTHENE-2-CARBOXAMIDE

Stages A through F are the same as those described in Example VIII.

Stage G. DextroN-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-5-amino-thianaphthene-2-carboxamide

In a 1 liter flask equipped with an agitator and a thermometer, thereare introduced 46 g of dextro 1-ethyl-2 -aminomethylpyrrolidine and 400ml of chloroform and the mixture is cooled to 5°C. There is added,fractionally, 3-methoxy-5-nitro-thianaphthene-2-carbonyl chloride, thetemperature being maintained at between 5° and 10°C. Where theintroduction is complete, the mixture is allowed to stand for one night.After the addition of 675 ml of water, the chloroform is distilled. Theresidue is then filtered with heat on charcoal. The hydrochloridecrystalizes on cooling. It is drained, washed with water and dried at50°C. There are obtained 135 g of product, melting at 145°-150°C.

The hydrochloride is dissolved in 600 ml of boiling water, the solutionis filtered with charcoal and alkalinized with 50 ml of ammonia. Theliquid base solidifies. It is drained, washed with water and dried at50°C. There are obtained 107 g of product, melting at 105°-108°C.

Stage H. DextroN-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-5-amino-thianaphthene-2-carboxamide

96 G (0.261 mole) of dextroN-(1-ethyl-2-pyrrolidylmethy)-3-methoxy-5-nitro-thianaphthene-2-carboxamidein 285 ml of water and 21.6 ml of concentrated hydrochloric acid in thepresence of 2 coffee spoons of Raney nickel under agitation arehydrogenated under pressure. After cooling, the nickel is filtered andthe base is precipitated by the addition of ammonia. It is then drained,washed with water and dried at 40°C. The base obtained is purified bysuccessive passage in dihydrochloride and then in the free base. Thereis obtained dextroN-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-5-amino-thianaphthene-2-carboxamidewith a rendering of 43% (m.p.: 104°-106°C); [α]_(D) =+ 45° (solution 5%dimethylformamide).

The acid addition salts of the 3-alkoxy-thianaphthene-2-carboxamides ofthis invention may be produced by reacting the carboxamide with amineral acid such as hydrobromic acid or an organic acid such as ethanesulfonic acid. The quaternary ammonium salts of such carboxamide may beproduced by reacting the carboxamide base with an aliphatic or aromaticalkylating agent, such as methyl chloride, methyl bromide, methyliodide, dimethyl sulfate, methyl benzene sulfonate, methyl p-toluenesulfonate, ethyl bromide, propyl bromide or benzyl chloride.

EXAMPLE XIIN-(1-ETHYL-2-PYRROLIDYLMETHYL)-3-METHOXY-5-CHLORO-THIANAPHTHENE-2-CARBOXAMIDEHYDROCHLORIDE

In a 3 liter flask equipped with an air-tight agitator, a solution ofsodium methylate is prepared by dissolving 12.65 g of sodium in 700 mlof methanol. 151 g of (2-carbomethoxy-methylthio)-5-methylchlorobenzoate are added fractionally. The mixture is allowed to reactwithout heating for one day and then 65 ml of acetic acid are addedwhich precipitates the 3-hydroxy-5-chlorothianaphthene-2-methylcarboxylate. It has a melting point of 158°C. The precipitate is washedand dried. It is placed in suspension in 625 ml of acetone with 71 g ofmethyl sulfate. It is heated to 40°C and 71 g of potassium carbonate areadded. It is refluxed for 3 hours. 500 ml of acetone are distilled andthe residue is recovered in 2 liters of water. The3-methoxy-5-chloro-thianaphthene-2-methyl carboxylate precipitates. Itis recovered and then dissolved in 500 ml of alcohol at 95°C. 51 ml of30% soda are added and reflux is maintained for one hour. Water is addedto dissolve the sodium salt formed and the insoluble traces arefiltered. The 3-methoxy-5-chloro-thianaphthene-2-carboxylic acid isprecipitated with 50 ml of concentrated hydrochloric acid. The 145 g ofacid obtained (0.6 mole) are introduced, in two portions, into a flaskcontaining 357 g of thionyl chloride. It is heated to 60°C to aiddissolution and then the second portion is added. It is refluxed toobtain the 3-methoxy-5chloro-thianaphthene-2-carbonyl chloride which iswashed with petroleum ether and dried.

Into a 1 liter flask, 36.5 g of 1-ethyl-2-aminomethyl pyrrolidinedissolved in 400 ml of methylethylketone are introduced. 74 g of acidchloride obtained above are added and heated to 30°C. When theintroduction is completed, a precipitate appears which crystallizes in30 minutes. It is filtered, washed with methylethylketone and dried at55°C. 95 g ofN-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-5-chloro-thianaphthene-2-carboxamidehydrochloride are obtained, having a melting point of 140°C. (Yield:86%)

EXAMPLE XIIIN-(MORPHOLINOPROPYL)-3-ETHOXY-5-BROMOTHIANAPHTHENE-2-CARBOXAMIDE-PHOSPHATE##SPC3##

Into a 250 ml flask, equipped with an air-tight agitator, an ascendingrefrigerant and a thermometer, there are introduced 30 g of3-ethoxy-5-bromothianaphthene-2-carboxylic acid. 36 ml of thionylchloride are added and the mixture is heated at 70°C for 2 hours. Theexcess of thionyl chloride is then removed to obtain 32 g of acidchloride melting at 117°-118°C.

In a 500 ml flask, 14.4 g of morpholinopropylamine are dissolved in 110ml of methylethylketone. The acid chloride is added under agitation andcooled at 0°C, avoiding going below 5°C. When the addition is complete,the temperature is allowed to go to 22°C. The crystals of hydrochlorideformed are dried and washed with 30 ml of methylethylketone. They aredissolved in 200 ml of water and the carboxamide is precipitated with 50ml of ammonia. It is extracted with sulfuric ether and the etherizedextracts washed in water. The ether is evaporated to obtain 26 g ofN-morpholinopropyl-3-ethoxy-5-bromothianaphthene-2-carboxamide.

The carboxamide is dissolved in 26 ml of absolute alcohol and 7 g oforthophosphoric acid dissolved in 10 ml of absolute alcohol are added.The mixture is cooled and agitated. The phosphate crystallizes. It isseparated, washed in alcohol and dried. Its melting point is 178°C.

EXAMPLE XIVN-(MORPHOLINOETHYL)-3-METHOXY-5NITRO-THIANAPHTHENE-2-CARBOXAMIDE##SPC4##

Into a 1 liter flask, equipped with a mechanical agitator and athermometer, are introduced 45 g of morpholinoethylamine dissolved in384 ml of chloroform. It is cooled to 3°C and 90 g of3-methoxy-5-nitro-thianaphthene-2-carboxyl chloride by fractions areintroduced, the temperature being maintained between 5° and 10°C.

When the introduction is completed, it is left under agitation at roomtemperature for 4 to 5 hours. It is allowed to stand for one night. TheN-(morpholinoethyl)-3-methoxy-5-nitro-thianaphthene-2-carboxamidecrystallizes. It is dried, washed with a little acetone and dried again.107 g of crystals are obtained, having a melting point of 250°C. (Yield:80%)

EXAMPLE XVN-(PYRROLIDINOETHYL)-3-ETHOXY-5-BROMO-THIANAPHTHENE-2-CARBOXAMIDEHYDROCHLORIDE

Into a 500 ml flask, equipped with a mechanical agitator, a thermometerand a dropping funnel, there are introduced 12 g ofpyrrolidinoethylamine dissolved in 150 ml of methylethylketone. It iscooled at 0°C and 32 g of 3-ethoxy-5-bromo-thianapthene-2-carboxylchloride are introduced fractionally, the temperature being maintainedbelow 10°C.

When the addition is complete, the mixture is agitated for one hour. Themethylethylketone is distilled under vacuum and the residue is recoveredwith ammonia to precipitate the base. It is extracted with chloroform,and after being washed in water, it is dried with an hydrous potassiumcarbonate. The chlororform is distilled to obtain the free base in theform of a red liquid.

The free base obtained[N-(pyrrolidinoethyl)-3-ethoxy-5-bromo-thianaphthene-2-carboxamide] isdissolved in absolute ethanol and the hydrochloride is obtained by theaddition of dry hydrochloric acid in ethanol. The precipitate obtainedis recrystallized twice to give 20 g of hydrochloride melting at 166°C.(Yield: 46%)

EXAMPLE XVIN-(PYRROLIDINOETHYL)-3-ETHOXY-5-NITRO-THIANAPHTHENE-2-CARBOXAMIDEHYDROCHLORIDE

In a 2 liter flask equipped with a mechanical agitator, there aredissolved 100 g of 3-hydroxy-5-nitro-thianaphthene-2-methyl carboxylatein 700 ml of methylethylketone and 79 g of an hydrous potassiumcarbonate are added. It is refluxed and 50 ml of dimethyl sulfate areadded. It is refluxed for 8 hours and is diluted with water toprecipitate 3-ethoxy-5-nitro-thianaphthene-2-methyl carboxylate. It iswashed in water and dried at 50°C.

In a 500 ml flask, 50 g of 3-ethoxy-5-nitro-thianaphthene-2-methylcarboxylate obtained as above, are agitated with 135 ml of ethanol, 110ml of water and 30 ml of sodium hydroxide at 36° Be. It is refluxed for2 hours, then poured into 300 ml of water and3-ethoxy-5-nitro-thianaphthene-2-carboxylic acid is precipitated with 40ml of hydrochloric acid, is washed and dried. The chloride of this acidis made by the addition of 100 ml of thionyl chloride to 39 g of acid.

20 g of pyrrolidinoethylamine are dissolved in 100 ml of chloroform andthis solution is cooled at 0°C. The acid chloride prepared above isintroduced, the temperature being maintained between 0° and 5°C. Theprecipitate is then agitated for 3 hours before drying and washing itwith a few milliliters of chloroform.

50 g ofN-(pyrrolidinoethyl)-3-ethoxy-5-nitro-thianaphthene-2-carboxamidehydrochloride are obtained, having a melting point of 210°C.

EXAMPLE XVIIN-(PYRROLIDINOETHYL)-3-ETHOXY-5-AMINO-THIANAPHTHENE-2-CARBOXAMIDEHYDROCHLORIDE

In a 1 liter autoclave, 50 g of hydrochloride obtained as above arecombined with 300 ml of water and 3 coffee spoonfuls of Raney nickel.Hydrogen is passed through to attain 120 kg of pressure, at 30°C. It isthen heated at 70°C and agitated for 3 hours before cooling. Thehydrogenation is then stopped, the nickel separated and the productsought precipitated with 50 ml of ammonia. The product is washed anddried. It has a melting point of 126°C.

Compositions of this invention have been pharmacologically studied todetermine their lack of toxicity on the one hand and their anti-emeticactivity and central nervous system activity on the other hand.

The low toxicities which were studied in the mouse showed that thecompositions of this invention have a toxicity entirely compatible withtherapeutic use. The results are given in the following table.

                    DL.sub.50 Base mg/kg                                          COMPOSITIONS    I.V.   I.P.   S.C.   P.O.                                     __________________________________________________________________________    N-(diethylaminoethyl)-3-                                                      methoxy-thianaphthene-2-                                                      carboxamide     25.8-29.5                                                                            105-114                                                                              164-168                                                                              273-286                                  N-(diethylaminoethyl)-3-                                                      methoxy-5-amino-thianaph-                                                     thene-2-carboxamide                                                                           49.9-52.6                                                                            109-112                                                                              125    242-273                                  N-(diethylaminoethyl)-                                                        3-5-6-trimethoxy-thia-                                                        naphthene-2-carboxamide                                                                       36.4-37                                                                              --     54-61.5                                                                              --                                       N-(1-ethyl-2-pyrrolidy-                                                       methyl)-3-methoxy-thianaph-                                                   thene-2-carboxamide                                                                           18.9-19.3                                                                            124-134                                                                              159    306-333                                  N-(1-ethyl-2-pyrrolidyl-                                                      methyl)-3-methoxy-5-                                                          aminothianaphthene-2-                                                         carboxamide     31.4-33.4                                                                            91.9-92.3                                                                            86.4-94.2                                                                            --                                       N-(1-ethyl-2-pyrrolidyl-                                                      methyl)-3-5-6-trimethoxy                                                      thianaphthene-2-carbox-                                                       amide           36-36.9                                                                              70-76  60-65  --                                       N-(diethylaminoethyl)-                                                        1-1-dioxy -3-methoxy-                                                         thianaphthene-2-carbox-                                                       amide           88     257-260                                                                              447-451                                                                              1106                                     N-(1-ethyl-2-pyrrolidyl-                                                      methyl)-1-1-dioxy -3-                                                         methoxy-thianaphthene-3-                                                      carboxamide     45.3   149-159                                                                              253-281                                                                              --                                       __________________________________________________________________________

The antimetic action of these compositions on the vomiting centers wasstudied in the dog with the aid of apomorphine following the techniqueof CHEN and ENSOR together with DUCROT and P. DECOURT. Lots of 4 dogswere worked with.

The apomorphine was administered subcutaneously in dosage of 0.10 mg/kg.The compositions studied were administered 30 minutes before, alsosubcutaneously. The vomitings were counted during the 30 minutesfollowing the injection of the apomorphine.

The following numbers were arrived at from the experimental results formany of the compositions of the present invention.

                              Rate of Protection                                                            in Dosages of 250 μg/kg                          COMPOSITIONS              Base                                                __________________________________________________________________________    N-(diethylaminoethyl)-3-methoxy-                                              thianaphthene-2-carboxamide                                                                             100%                                                N-(dimethylaminoethyl)-3-methoxy-5-amino-                                     thianaphthene-2-carboxamide                                                                             100%                                                N-(diethylaminoethyl)-3-methoxy-5-amino-                                      thianaphthene-2-carboxamide                                                                             100%                                                N-(diethylaminoethyl)-3-5-6-trimethoxy-                                       thianaphthene-2-carboxamide                                                                             100%                                                N-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-                                     thianaphthene-2-carboxamide                                                                             100%                                                N-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-5-                                   amino-thianaphthene-2-carboxamide                                             (Racemic mixture of levo and dextro forms)                                                              100%                                                N-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-5-                                   amino-thianaphthene-2-carboxamide (levo                                       form)                     100%                                                N-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-5-                                   amino-thianaphthene-2-carboxamide (dextro                                     form)                     100%                                                N-1-ethyl-2-pyrrolidylmethyl)-3-5-6-trimethoxy-                               thianaphthene-2-carboxamide                                                                             100%                                                N-(diethylaminoethyl)-1-dioxy -3-methoxy-                                     thianaphthene-2-carboxamide                                                                             100%                                                N-(1-ethyl-2-pyrrolidylmethyl)-1-dioxy -3-                                    methoxy-thianaphthene-2-carboxamide                                                                     100%                                                __________________________________________________________________________

Other pharmacological properties of these compositions were proved bymeans of various tests which showed their excellent modifying action onthe central nervous system. These tests are summarized in the followingtables for many of the compositions of this invention.

    ______________________________________                                        CATALEPTIC ACTIVITY IN THE MOUSE                                              ______________________________________                                                                   DE.sub.50 Base                                     COMPOSITIONS               mg/kg/S.C.                                         ______________________________________                                        N-(diethylaminoethyl)-3-methoxy-thianaphthene-                                2-carboxamide              15.9 (7 h)                                         N-(diethylaminoethyl)-3-methoxy-5-amino-                                      thianaphthene-2-carboxamide                                                                              --                                                 N-(diethylaminoethyl)-3-5-6-trimethoxy-                                       thianaphthene-2-carboxamide                                                                              --                                                 N-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-                                     thianaphthene-2-carboxamide                                                                              2-2.2 (6 h)                                        N-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-5-                                   amino-thianaphthene-2-carboxamide                                                                        17.3 (7 h)                                         N-(1-ethyl-2-pyrrolidylmethyl)-3-5-6-                                         trimethoxy-thianaphthene-2-carboxamide                                                                   8 (7 h)                                            N-(diethylaminoethyl)-1-dioxy -3-                                             methoxy-thianaphthene-2-carboxamide                                                                      --                                                 N-(1-ethyl-2-pyrrolidylmethyl)-1-1-                                           dioxy -3-methoxy-thianaphthene-2-carboxamide                                                             13.6 (7 h)                                         ______________________________________                                    

    ACTION ON MOTILITY OF THE MOUSE                                               (TEST OF WINTER AND FLATAKER)                                                 __________________________________________________________________________                                 DE.sub.50 Base                                   COMPOSITIONS                 mg/kg/I.P.                                       __________________________________________________________________________    N-(diethylaminoethyl)-3-methoxy-thianaphthene-2-                              carboxamide                  14.1                                             N-(diethylamino)-3-methoxy-5-amino-thianaphthene-                             2-carboxamide                 8.6                                             N-(diethylaminoethyl)-3-5-6-trimethoxy-thianaphthene-                         2-carboxamide                --                                               N-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-                                     thianaphthene-2-carboxamide  1.9-2.5                                          N-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-5-                                   amino-thianaphthene-2-carboxamide                                                                          2.9-3.1                                          N-(1-ethyl-2-pyrrolidylmethyl)-3-5-6-trimethoxy-                              thianaphthene-2-carboxamide  31-34                                            N-(diethylaminoethyl)-1-1-dioxy -3-methoxy-                                   thianaphthene-2-carboxamide  97.5                                             N-(1-ethyl-2-pyrrolidylmethyl)-1-1-dioxy -3-methoxy-                          thianaphthene-2-carboxamide  76.1-78.8                                        __________________________________________________________________________

    ACTION OF THE MOTILITY OF THE MOUSE                                           (ACTION GRAPH OF KRAUTHAMER)                                                  __________________________________________________________________________                                DE.sub.50 Base                                    COMPOSITIONS                mg/kg I.P.                                        __________________________________________________________________________    N-(diethylaminoethyl)-3-methoxy-thianaphthene-2-                              carboxamide                 6.4-6.8                                           N-(diethylaminoethyl)-3-methoxy-5-amino-                                      thianaphthene-2-carboxamide --                                                N-(diethylaminoethyl)-3-5-6-trimethoxy-                                       thianaphthene-2-carboxamide 17.8                                              N-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-                                     thianaphthene-2-carboxamide 1.3                                               N-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-5-amino-                             thianaphthene-2-carboxamide --                                                N-(1-ethyl-2-pyrrolidylmethyl)3-5-6-trimethoxy-                               thianaphthene-2-carboxamide 18                                                N-(diethylaminoethyl)-1-1-dioxy -3-methoxy-                                   thianaphthene-2-carboxamide --                                                N-(1-ethyl-2-pyrrolidylmethyl)-1-1-dioxy -3-methoxy-                                                      63.4                                              thianaphthene-2-carboxamide 65.2                                              __________________________________________________________________________

    TEST OF BODY TURNING IN THE MOUSE                                             __________________________________________________________________________                      DE.sub.50 Base                                              COMPOSITIONS      mg/kg/I.P.  OBSERVATIONS                                    __________________________________________________________________________    N-(diethylaminoethyl)-3-                                                      methoxy-thianaphthene-2-                                                      carboxamide        28 (10 mn)                                                 N-(diethylaminoethyl)-3-                                                      methoxy-5-amino-thianaphthene                                                 2-carboxamide     31.2 (10 mn)                                                N-(diethylaminoethyl)3-5-6-                                                   trimethoxy-thianaphthene-2-                                                   carboxamide                    20 mg/kg: effect of                                                          5%                                              N-(1-ethyl-2-pyrrolidylmethyl)                                                3-methoxy-thianaphthene-2-                                                    carboxamide       13-16.8 (10 mn)                                             N-(1-ethyl-2-pyrrolidylmethyl)                                                3-methoxy-5-amino-thianaphthene-                                              2-carboxamide     25.1-23.2                                                   N-(1-ethyl-2-pyrrolidylmethyl)                                                3-5-6-trimethoxy-thianaphthene-                                               2-carboxamide     39.5 (10mn)                                                 N-(diethylaminoethyl)-1-1-                                                    dioxy -3-methoxy-thianaphthene-                                               2-carboxamide                 100 mg/kg: effect of                                                          17%                                             N-(1-ethyl-2-pyrrolidylmethyl)-                                               1-1-dioxy -3-methoxy-                                                         thianaphthene-2-carboxamide    60 mg/kg: effect of                                                          0%                                              __________________________________________________________________________

    TEST OF TRACTION IN THE MOUSE                                                 (COURVOISIER - JULOU)                                                         __________________________________________________________________________                         DE.sub.50 Base                                           COMPOSITIONS         mg/kg S.C.                                                                           OBSERVATIONS                                      __________________________________________________________________________    N-(diethylaminoethyl)-3-methoxy-                                              thianaphthene-2-carboxamide                                                                        40.9                                                     N-(diethylaminoethyl)-3-methoxy-                                              5-amino-thianaphthene-2-                                                      carboxamide                 100 mg/kg: effect of 20%                          N-(diethylamino)-3-5-6-trimethoxy-                                            thianaphthene-2-carboxamide 30 mg/kg: effect of 30%                           N-(1-ethyl-2-pyrrolidylmethyl)-3-                                             methoxy-thianaphthene-2-carboxamide                                                                46                                                       N-(1-ethyl-2-pyrrolidylmethyl)-                                               3-methoxy-5-aminothianaphthene-2-                                             carboxamide                 40 mg/kg: effect of 0%                            N-(1-ethyl-2-pyrrolidylmethyl)-3-5-6-                                         trimethoxy-thianaphthene-2-carboxamide                                                                    40 mg/kg: effect of 33%                           N-(diethylaminoethyl)-1-1-dioxy-                                              3-methoxy-thianaphthene-2-carboxamide                                                                     200 mg/kg: effect of 10%                          N-(1-ethyl-2-pyrrolidylmethyl)-1-1-                                           dioxy -3-methoxy-thianaphthene-2-                                             carboxamide                 80 mg/kg: effect of 0%                            __________________________________________________________________________

    INFLUENCE ON THE BARBITURIC NARCOSIS IN THE                                   MOUSE                                                                         __________________________________________________________________________                     DE.sub.50 Base*                                              COMPOSITIONS     mg/kg/I.P.                                                                            OBSERVATIONS                                         __________________________________________________________________________    N-(diethylaminoethyl)-3-                                                      methoxy-thianaphthene-2-                                                      carboxamide              40 mg/kg: index = 1.18                               N-(diethylaminoethyl)-3-                                                      methoxy-5-amino-thianaphthene-                                                2-carboxamide    31.2 (30 mn)                                                 N-(diethylaminoethyl)-3-5-6-                                                  trimethoxy-thianaphthene-2-                                                   carboxamide              20 mg/kg: index = 1.46                               N-(1-ethyl-2-pyrrolidyl-                                                      methyl)-3-methoxy-                                                            thianaphthene-2-carboxamide                                                                            40 mg/kg: index = 0.76                               N-(1-ethyl-2-pyrrolidyl-                                                      methyl)-3-methoxy-5-amino-                                                    thianaphthene-2-carboxamide                                                                    78- 86.4                                                     N-(1-ethyl-2-pyrrolidyl-                                                      methyl)-3-5-6-trimethoxy-                                                     thianaphthene-2-carboxamide                                                                            40 mg/kg: index = 1.06                               N-(diethylaminoethyl)-1-1-                                                    dioxy -3-methoxy-                                                             thianaphthene-2-carboxamide                                                                     181 (30 mn)                                                 N-(ethyl-2-pyrrolidyl-                                                        methyl)-1-1-dioxy -3-                                                         methoxy-thianaphthene-2-                                                      carboxamide              100 mg/kg: index = 1.81                              __________________________________________________________________________     *Dose corresponding to index 2 (doubling of time of hypnosis).           

    TEST WITH APOMORPHINE IN THE RAT                                              (JANSSEN)                                                                     __________________________________________________________________________                       DE.sub.50 Base                                             COMPOSITIONS       mg/kg/S.C.                                                                            OBSERVATIONS                                       __________________________________________________________________________    N-(diethylaminoethyl)-3-                                                      methoxy-thianaphthene-2-                                                      carboxamide        30.3-35.6                                                  N-(diethylaminoethyl)-3-                                                      methoxy-5-amino-thianaphthene-                                                2-carboxamide      76.4-77.9                                                  N-(diethylaminoethyl)-3-5-6-                                                  trimethoxy-thianaphthene-2-                                                   carboxamide        72                                                         N-(1-ethyl-2-pyrrolidylmethyl)-3-                                             methoxy-thianaphthene-2-                                                      carboxamide        4.05-4.7                                                   N-(1-ethyl-2-pyrrolidylmethyl)-3-                                             methoxy-5-aminothianaphthene-2-                                               carboxamide         6-7.1                                                     N-(1-ethyl-2-pyrrolidylmethyl)-3-                                             5-6-trimethoxy-thianaphthene-2-                                               carboxamide        26.5-30                                                    N-(diethylaminoethyl)-1-1-                                                    dioxy -3-methoxy-                                                             thianaphthene-2-carboxamide                                                                              200 mg/kg: effect of 0%                            N-(1-ethyl-2-pyrrolidylmethyl)-1-                                             1-dioxy -3-methoxy-thianaphthene-                                             2-carboxamide              200 mg/kg: effect of 0%                            __________________________________________________________________________

    TEST WITH MORPHINE IN THE MOUSE                                               __________________________________________________________________________                       DE.sub.50 Base                                             COMPOSITIONS       mg/kg/P.O.                                                                           OBSERVATIONS                                        __________________________________________________________________________    N-(diethylaminoethyl)-3-                                                      methoxy-thianaphthene-2-                                                      carboxamide        --                                                         N-(diethylaminoethyl)-3-                                                      methoxy-5-amino-                                                              thianaphthene-2-                                                              carboxamide        --                                                         N-(diethylaminoethyl)-3-5-6-                                                  trimethoxy-thianaphthene-2-                                                   carboxamide        --                                                         N-(1-ethyl-2-pyrrolidylmethyl)-3-                                             methoxy-thianaphthene-2-                                                      carboxamide        42                                                         N-(1-ethyl-2-pyrrolidylmethyl)-3-                                             methoxy-5-amino-thianaphthene-2-                                              carboxamide        62.8                                                       N-(1-ethyl-2-pyrrolidylmethyl)-3-                                             5-6-trimethoxy-thianaphthene-2-                                               carboxamide        --                                                         N-(diethylaminoethyl)-1-1-                                                    dioxy -3-methoxy-                                                             thianaphthene-2-carboxamide                                                                      --                                                         N-(1-ethyl-2-pyrrolidylmethyl)-1-                                             1-dioxy -3-methoxy-thianaphthene-                                             2-carboxamide             400 mg/kg: effect of 38%                            __________________________________________________________________________

    TEST WITH TREMORINE IN THE MOUSE                                              __________________________________________________________________________                       DE.sub.50 Base                                             COMPOSITIONS       mg/kg/I.P.                                                                           OBSERVATIONS                                        __________________________________________________________________________    N-(diethylaminoethyl)-3-                                                      methoxy-thianaphthene-2-                                                      carboxamide               400 mg/kg: effect of 5%                             N-(diethylaminoethyl)-3-                                                      methoxy-5-amino-thianaphthene-                                                2-carboxamide             80 mg/kg: effect of 28%                             N-(diethylaminoethyl)-3-5-6-                                                  trimethoxy-thianaphthene-2-                                                   carboxamide        --                                                         N-(1-ethyl-2-pyrrolidylmethyl)-3-                                             methoxy-thianaphthene-2-                                                      carboxamide               40 mg/kg: mg/kg: effect of 10%                      N-(1-ethyl-2-pyrrolidylmethyl)-3-                                             methoxy-5-amino-thianaphthene-2-                                              carboxamide               60 mg/kg: effect of 11%                             N-(1-ethyl-2-pyrrolidylmethyl-3-                                              5-6-trimethoxy-thianaphthene-2-                                               carboxamide               30 mg/kg: effect of 21%                             N-(diethylaminoethyl)-1-1-dioxy-                                              3-methoxy-thianaphthene-2-                                                    carboxamide               100 mg/kg: effect of 16%                            N-(1-ethyl-2-pyrrolidylmethyl)-1-                                             1-dioxy -3-methoxy-thianaphthene-                                             2-carboxamide             80 mg/kg: effect of 5%                              __________________________________________________________________________

The experimental results have been confirmed in the clinic where theproducts were administered in the form of tablets or ampoules of apharmaceutically acceptable salt.

Treatments were made under clinical conditions in accordance withpharmacodynamics, with no manifestation of medicament intolerance.

The compositions of this invention can be administered in the form of apharmaceutically acceptable salt in pills, injectable or aerosolampoules, suppositories, granulated sweetener and sweetened syrup.

These medicaments may be administered in the form of ampules, tablets,drops or in drinkable solutions containing pharmaceutically acceptablesalts of a compound of this invention. The compounds of this inventionwith or without other compatible therapeutic ingredients, fillers oradjuvents may be conveniently administered in dosage unit forms. Forexample, the following formulation may be used for compressed tabletdosage form:

    active ingredient   60 mg                                                     spray dried lactose 266 mg                                                    starch              20 mg                                                     magnesium stearate   4 mg                                                 

The spray dried lactose, magnesium stearate, starch and activeingredient may be mixed uniformly and then compressed directly intotablets.

For use in capsule dosage form, the active ingredient may be mixed witha suitable quantity of lactose until uniform and the capsules may befilled either by hand or by suitable mechanical means. A capsuleformulation is as follows:

    active ingredient   75 mg                                                     lactose q. s. to 300                                                      

The daily dosage may vary over wide limits for the treatment of emesisor behavior disturbances as determined by the veterinarian or physician.Desirably, the daily dosage may range from 50 to 500 μg/kg.

What is claimed is:
 1. A method of protecting a mammal against emesiswhich comprises administering to said mammal an anti-emesis effectiveamount of a compound selected from the group consisting of a3-alkoxy-thianaphthene-2-carboxamide, the dioxides thereof, thepharmaceutically acceptable acid addition salts and quaternary ammoniumsalts thereof, said 3-alkoxy-thianaphthene-2-carboxamide having theformula: ##SPC5##in which R₁ and R₂ are the same or different and arehydrogen, lower alkoxy, halogen, nitro or amino; B is lower alkyl orallyl; n is 1, 2 or 3; and A is mono lower alkylamino or di loweralkylamino.
 2. The method of claim 1 in which said compound is acompound in which A of the formula is diethylamino.
 3. The method ofclaim 1 in which said compound is a compound in which A of the formulais dimethylamino.
 4. The method of claim 1 in which said compound isN-(diethylaminoethyl)-3-methoxy-thianaphthene-2-carboxamide.
 5. Themethod of claim 1 in which said compound isN-(diethylaminoethyl)-3-methoxy-5-amino-thianaphthene-2-carboxamide. 6.The method of claim 1 in which said compound isN-(dimethylaminoethyl)-3-5-6-trimethoxy-thianaphthene-2-carboxamide. 7.The method of claim 1 in which said compound isN-(diethylaminoethyl)-1,1-dioxy-3-methoxy-thianaphthene-2-carboxamide.8. The method of claim 1 in which said compound is a levo or dextrorotary isomer.